Cocrystal components

As part of a more extensive study of cocrystals formed by isonicotinamide with carboxylic acids, 1 1 products containing the dicarboxylic fumaric or succinic acids [59]. In the structures of these particular cocrystals, the typical discrete dimeric synthon was not observed, but instead effectively infinite assemblies of one-dimensional chains were found instead. In a subsequent work, cocrystals of isonicotinamide containing mixed fumaric/succinic acids were prepared using both solid-state grinding and solution crystallization [60]. A full physical characterization of the products demonstrated that the products consisted of a single cocrystal phase, and were not simple physical mixtures of two cocrystal components. Such solid solutions were proposed as yet another method whereby one might obtain even finer control over the physical properties of cocrystal systems proposed as drug substances. 

S.J. Bethune, N. Huang, A. Jayasankar, N. Rodriguez-Homedo, Understanding and predicting the effect of cocrystal components and pH on cocrystal solubility, Cryst. Growth Des. 9 (2009) 3976-3988. 

We will first describe some of the theoretical aspects for cocrystal design, followed by a summary of the pharmaceutical properties of cocrystals, including their solubility dependence on cocrystal component concentration and in some cases on solution pH. Processes for cocrystal formation will be presented by considering the factors that control cocrystallization kinetics and mechanisms in solution and in solid-state mediated processes. This article will be useful to the reader who wishes to anticipate cocrystal formation during pharmaceutical processes and storage and to those who wish to proactively discover new phases. 

The solubility of a binary cocrystal of API (A) and ligand or cocrystal component (B), of composition Aa Bb where the cocrystal components do not ionize or form complexes in solution, is given by the equilibrium reaction... 

This equation predicts that addition of either cocrystal component to a solution in excess of S decreases the cocrystal solubility when the preceding conditions apply. A plot of the solubility of cocrystal A B as a function of total ligand in solution according to Eq. (9) is shown in Fig. 12. 

Also shown in Fig. 12 is the solubility of single component crystal of A, as a function of cocrystal component or ligand (B) concentration in solution. This phase diagram is based on the following assumptions (i) A is less soluble than B (ii) A is less soluble than A B in stoichiometric solutions (with... 

The transition concentration of cocrystal component can be predicted by substituting the single component crystal solubility, Sa, for the cocrystal solubility, S, in Eq. (7) and rearranging to give... 

Fig. 15 compares the experimental and predicted cocrystal solubilities had solution complexation been neglected, according to Eq. (25). This analysis shows that 1 1 solution complexation of cocrystal components increases the solubility of a 1 1 cocrystal by a constant, which is the product of K p and ATn. Thus, when the solubility of cocrystal is known only in pure solvent, the K p estimate is useful in assessing the dependence of cocrystal solubility on ligand concentrations. This is valuable in identifying the ligand concentrations in pharmaceutical processes and formulations where cocrystal formation can occur. 

The most generally used solution-based method to synthesize cocrystals is slow evaporation from solutions with equimolar or stoichiometric concentrations of cocrystal components.f Solvo-thermal methods are also reported in the literature, although less frequently. ° In this method, heat is used to dissolve stoichiometric amounts of both components, the solution is cooled, and the cocrystals are then allowed to nucleate and grow. These processes, however, suffer from the risk of crystallizing the single component phases, thereby reducing the possibility of isolating the multiple component crystalline phase. As a result... 

We have recently developed methods where nucleation and growth of cocrystals are directed by the effect of the cocrystal components on reducing the solubility of the molecular complex to be crystallized. The supersaturation, a, with respect to cocrystal is derived from the difference in chemical potential between the cocrystal components in the supersaturated solution state and in the solid state and is given by... 

Based on these concepts a reaction crystallization process may be designed such that the solution is supersaturated with respect to cocrystal only, while it is below, or, at saturation with respect to the individual components. Supersaturation can be generated by various approaches according to the solubility product behavior. These processes include (i) mixing solutions of reactants or cocrystal components in non-stoichiometric concentrations or (ii) dissolving one or more solid reactants so that non-stoichiometric conditions are generated. 

Solution stability is a very important parameter to assess during development and for this discussion will be defined as the ability of the co-crystal components to stay in solution and not readily crystallize or precipitate. A variety of media can be introduced, including water, simulated gastric fluid (SGF), simulated intestinal fluid (SIF), formulation vehicles, and buffered solutions. In many instances, these experiments can be coupled with solubility or dissolution experiments to obtain a more complete picture of the behavior and the solid form remaining at the end of the experiment. Because dissociation of a cocrystal often occurs and precipitation of a less soluble form (either one of the components or another co-crystal) can result, solution stability studies should be considered early in development of a potential drug product. Attention has been focused on formulation approaches to stabilize the co-crystal (or cocrystal components) in solution by addition of surfactants to avoid the problem of recrystallization. One of the first reports on this approach was published by Remenar et al. on a celecoxibmicotinamide co-crystal in various formulation vehicles (110% sodium dodecylsulfate (SDS) and polyvinylpyrrolidone (PVP)) in order to understand the solid form that may result upon contact with... 

Co-crystal and drug solubility surfaces intersect at a given pH value and solution concentrations of R and A. Two important charaeteristics of the intersection points are that (1) two solid phases (in this case, co-crystal and drug) coexist in equilibrium with solution, and (2) solution composition of cocrystal components ([R]eu and [A]eu) is fixed at a given pH and temperature,... 

By using co-crystallization via halogen bonding and other assisting interactions, ten cocrystals between PAHs and their heterocyclic analogues and haloperfluoro-benzenes were successfully assembled. The structures and cocrystal components are shown in Scheme 1 and Table 1. 

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